Département de chimie moléculaire

The synthesis of 1,3,6-trisubstituted-2,5-diketopiperazine scaffolds bearing up to three click chem. sites for further oxime bond or alkyne-azide cycloaddn. ligations is described. The orthogonally BOC/Alloc protected DKP precursors prepd. from L-lysine residues and an (amino)hexane arm are efficiently prepd. on a gram scale by sequentially using Fukuyama-Mitsunobu alkylation, dipeptide coupling and diketopiperazine ring formation as key steps. These scaffolds, with their glyoxylyl, aminooxy, alkynyl or azido functions, are ready-to-use-platforms for biomol. assembly. Their potentiality in this field was proved through the chemoselective ligation of A$\beta$-binding motifs, the KLVFFA peptide and a curcumin compd. The inhibitory effect of these conjugates on A$\beta$ amyloid fibril formation is reported using thioflavin T fluorescence assays and AFM observation. The title compds. thus formed included a chiral diketopiperazine deriv. (DKP, cyclic dipeptide Lys-Lys) (I) which was elaborated further to provide $\beta$-amyloid inhibitors (anti-Alzheimer agents). [on SciFinder(R)]